This systematic review and meta-analysis does not differentiate among HA-based products. All of them are considered together as a single class of compounds sharing a common MOA (viscosupplementation). Instead, the considered HA-based preparations for intra-articular administration exhibit significant differences in HA concentration, MW and in protocol of injection. They also differ in terms of molecular organization, since the considered pool includes solutions of native HA, as materials chemically derived from HA, engineered to increase elastoviscosity and intra-articular residence time. In the last decades increasing evidence was provided indicating that these characteristics significantly affect the main MOA a HA-based product may exhibit. It is well known that the biophysical features (viscoelasticity, lubrication) of the injected solution are dependent on MW and become more efficient with increasing chain length. On the other side, the diffusion in the tissues was shown to increase with decreasing MW [1], replacing OA synovial fluid with higher HA concentration increasing HA viscosity, restoring shock-absorbing, lubricating ability of depleted synovial fluid [2][3] and maintaining boundary layer around nociceptors, reducing pain induction. Thus, based on the characteristics of the HA used, each preparation for intra-articular therapy is likely endowed of a specific profile as a therapeutic tool, with its own characteristics (MOA mainly mechanical or biological, target patient, treatment schedule, time to reach some effect and so on). Similar considerations can be done regarding the safety. Studies are available, for instance, estimating an incidence of AEs of 0.5-0.8% for preparations based on native HA [4] and of more than 8% for chemically modified HA [5]. Thus, possible differences in the efficacy and safety profile specific to each product, may affect the results of the statistical analyses performed on the category as a whole, as recently pointed out in the available literature by several authors [6,7]. The suggestion is that meta-analyses pooling all HA preparations into one single class may dilute the effect sizes of more efficacious preparations to estimate, definitely by excellent methods, a sort of “average” behavior within a significantly inhomogeneous group of tools. Such result can provide only limited information from a pharmacological and therapeutic perspective. From clinical perspective, IAHA therapy is a powerful weapon in the hands of healthcare providers (orthopedists, rheumatologists, general practitioners) giving the patients relief from disabling joints pain. Most of the patients are aged, with comorbidities, and disabling joint osteoarthritis obliging them to chronic assumption of oral drugs, often with side dangerous effects on heart, liver and kidney. IAHA cannot heal these patients but can provide pain relief and improvement of joint motion when cyclic treatments are adopted. Furthermore, many patients cannot undergo surgery, and IAHA remains a reliable alternative to alleviate pain, as the way to post-pone surgery if needed. Pain relieving action of the injected HA is assumed by the increased extracellular matrix protein synthesis, the modification of inflammatory mediators to prevent degradation, the limitation of lymphocyte motility, and by the preservation cartilage thickness, area and surface smoothness [8]. Indications remain the most important factors to achieve satisfactory results, as well as the choice of the appropriate formulation and molecular weight of HA. Therefore, the efficacy and safety of the IAHA treatment must be demonstrated with well-designed clinical trials, defining indications, level of diseases, patient’s phenotype, according to the different available molecules, and treatment regimens, in particular on the treatment of knee osteoarthritis, which has been the most investigated. It has been well demonstrated that the efficacy of IAHA therapy varies widely across the different preparations [7-10]. The recommendations not to use this therapy, when safety and efficacy have been well documented, should be based upon different type of investigations.

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Competing interests: No competing interests